The quest for sustainable pills
100 kilos of waste for 1 kilo of drugs
Few industries are quite as polluting as that of pharmaceuticals. Chemical materials that are produced on a large scale, such as acetic acid or ethanol, produce approximately one to five kilos of waste for every kilo of product. The oil industry, although it doesn’t have the best reputation, only produces 100 grams of waste per kilo of product.
‘But the pharmaceutical industry’s environmental factor is 25 to 100’, says professor of pharmaceutical biotechnology Gerrit Poelarends. That means that every kilo of drugs that’s being produced creates approximately 25 to 100 kilos of waste.
That means the pharmaceutical industry, while smaller than other industries, is one of the most polluting industries in the world per kilo.
If all that medical waste enters the environment, it can lead to death or behavioural changes in fish and other aquatic animals. These fish can then end up on people’s plates. ‘There are plenty of reasons to try and diminish the amount of waste’, says Poelarends. ‘I think they should try for the 1 to 5 kilograms other industries produce.’
I think they should try for the 1 to 5 kilograms other industries produce
Poelarends has made it his mission to contribute to the realisation of this goal. He not only tries to find alternative drug options, but also tries to find different ways to produce already existing drugs.
‘There are several steps in the chemical process to create drugs’, he explains. ‘Sometimes as many as eleven for a single active molecule. The solvents being used may ensure that the process runs smoothly, but they’re also very harmful. And these substances are thrown out after every use.’
The solution seems simple: reduce the number of steps in the process. Poelarends says we should also abolish the use of harmful solvents. ‘Developing a simpler synthesis route could help with that.’ While each step usually only results in one change in the molecule, the new method would make several changes.
Another solution would be to no longer use chemical substances for the reactions but use enzymes instead. These can also aid in chemical reactions, but can be found in plant, animal, and bacterial cells. And unlike most chemical substances, they don’t have to be extracted from devastating mines or petroleum.
That’s not all: in contrast to many chemical substances, enzymes can repeat the same step over and over again. The third and final advantage is that enzymes are usually water soluble. That means they can replace harmful solvents.
Poelarends has already proven that his strategy works through his greener production of TBOA. This is a substance that can block nerve transmissions in the brains and is used a lot in research into how certain nerve cells work. ‘You’d normally go through eleven steps to create this molecule, but the greener process does it in three.’
Normally, you’d go through eleven steps to create this molecule, but now it’s three
Poelarends wants to make the same change in drug production; he was awarded a prestigious Vici grant for earlier research results in 2017.
In creating ‘green’ drugs, however, he encountered another problem: patents. After a pharmaceutical company has created a drug, they’ll have time to earn back the high production costs. During that period, no one is allowed to make the same drug.
‘But every patent runs out eventually’, says Poelarends. ‘We regularly check which drugs are becoming patent-free within five years and if we have any options to make them greener and more sustainable.’
In 2018, a year after receiving his Vici grant, he worked on pregabalin, a promising substance that works to combat nerve pain, among other things. ‘It’s one of the most popular drugs in the world’, says Poelarends. ‘The industry is therefore very interested in making its production process greener.’
Poelarends went to work, only to find out that it wasn’t easy. For the longest time, researchers thought that reactions could only happen one of two different ways. Either through metal catalysis, using metals as catalysts, or the greener route, using enzymes. ‘But that didn’t work, because nature doesn’t have a supply of ready-made enzymes to produce pregabalin.’
But a discovery that led to a 2021 Nobel Prize win for chemistry turned out to benefit Poelarends as well. There turned out to be a third option: organocatalysis. ‘This involves using a small organic molecule as a catalyst to get the chemical reaction started. By adding that same molecule to an enzyme, you can then use the enzyme to speed up other reactions.’
It’s important that the drug molecule’s shape matches the enzyme, like a key fitting into a lock. The enzyme Poelarends wanted to use wasn’t suitable to perform the step in the reaction because the enzyme and the previous version of the drug didn’t match up, but thanks to the new link, it now was.
Poelarends’ bridge is formed by the amino acid proline. Suddenly, he was able to take that first step towards pregabalin. ‘It was a crucial step in the process.’
How big is the impact on the environment, how long will the residue be present?
The second step also went according to plan. To achieve it, Poelarends struck up a partnership with a company that can design enzymes. When he’ll be able to achieve the third step, in which the nitro compound is converted into an amine, Poelarends doesn’t know yet. ‘That’s a very difficult step, enzymatically speaking, but we hope to achieve it by the end of this year’, he says.
If at all possible, Poelarends would like to combine the three steps into a single big one. He’d be able to do this by incorporating the three enzymes he needs in a bacterium. ‘It’s like making a small factory that can perform all the steps in sequence in the same vessel.’ At the end of the process, Poelarends would simply filter the bacteria from the water, leaving behind only the drug, skipping all kinds of complicated cleaning steps. ‘It’s also a lot cleaner and cheaper.’
Poelarends is already focused on the future. Not only does drug production harm the environment, but the residue left by pills and powders often ends up in the surface water, which once again negatively affects wildlife and people.
‘I would love it if drugs were easily biodegradable’, he says. ‘But that would also mean they easily break down inside the body.’ That’s not necessarily a good thing.
Research would also have to be done into the effect of drug residue. ‘How big is the potential damage to the environment, how long will the residue stay in the environment, and what can we do about that when designing drugs?’
He’s thinking about setting up a database of drugs that easily dissolve in the environment. ‘Perhaps we can use artificial intelligence to help predict how new medication can be sustainably and safely designed in the future. The drug and water treatment industries in the Netherlands are certainly interested.’
New master of sustainable drug discovery
In addition to his research, Poelarends and his colleague, professor of pharmacoepidemiology and educational director Eelko Hak, contributed to the creation of a new European master programme on sustainable drug development. The UG is working together with the universities of Ghent, Lille, and Gdansk.
The universities received 5.1 million euros in EU subsidies for the programme, and prospective students will receive financial support. The programme will start in September of this year.